The present invention generally relates to medical treatments. The invention particularly relates to modulating current activity in T-type calcium channels in a subject to treat pain and other conditions.
Transient opening (“T-type”) calcium channels are low-voltage activated calcium channels that open during membrane depolarization. These channels aid in mediating calcium influx into cells and depolarizing the membrane in order to induce an action potential. They can also mediate calcium influx after an action potential or depolarizing signal. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac and smooth muscle cells, voltage-gated calcium channel activation directly initiates contraction by allowing the cytosolic calcium concentration to increase. In addition to their presence within cardiac and smooth muscle, T-type calcium channels are also known to be present in many neuronal cells within the central nervous system. T-type calcium channels are distinct from L-type (long-lasting) calcium channels as T-type channels are activated by more negative membrane potentials (low voltage-activated, LVA), have small single channel conductance, and are generally unresponsive to conventional calcium antagonist drugs directed to L-type calcium channels. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.
There are several lines of evidence that support the claim that T-type channel modulation has an effect on pain sensation. Overall, when neuronal excitability is low, T-type currents are activated to increase excitability. These channels are encoded for by different genes; CACNA1G, CACNA1H, and CACNA1I, which encode for the principal T-type channel subunits alpha1G, alpha1H and alpha1I. These genes are expressed in neurons, however, they are not usually expressed at the same levels. For instance, alpha1G and alpha1H T-type calcium channel expression is higher in the back of the spinal cord, and alpha1G is more abundant than alpha1H in thalamocortical relay neurons. In dorsal root ganglia (DRG) in the peripheral nerves, alpha1H function is related to hyperalgesic reaction against thermo-stimuli or mechanical stimuli and recent results strongly implicate T-channels in the processing of nociceptive signals in both the peripheral and central nervous systems. It is known that in-vivo silencing of the CaV3.2 T-type calcium channels in sensory neurons results in antiallodynic and analgesic effects in rat models of both acute thermal and mechanical pain. Local injection of CaV3.2 antisense oligonucleotides also causes significant and long-term attenuation of induced neuropathic hypersensitivity. CACNA1H T-type channel KO mice exhibit attenuated responses to mechanical, thermal, and chemical cutaneous pain stimuli and chemical visceral pain stimuli.
Most conventional methods for modulating T-type channel activity are performed by administering drugs that generally include a T-type calcium channel inhibitor as an effective ingredient. Usually, these drugs are modifications of already known channel blockers. For example, mibefradil is a drug that targets T-type channels, but unfortunately also affects other types of channels as well, such as high voltage-activated (HVA) channels. As such, it has currently been withdrawn from commercial sale apparently due to its undesirable side effects and drug interactions.
Conventional methods and drugs target T-type channels directly for the treatment of pain. A major problem of this approach is that T-type channels are present in most excitable cells, including neurons and cardiac cells. Therefore, their direct targeting can cause unwanted side effects, some of which may be lethal. Similarly, available chemicals that target T-type channels are not selective, and can also affect other types of channels, for example HVA channels, with serious consequences.
Accordingly, there is a desire for methods and compounds capable of modulating T-type channel activity that avoids these adverse side effects.